Advances in PTH-based Medicines

Abstract

Parathyroid hormone (PTH), produced by the parathyroid glands, plays a critical role in the regulation of calcium and phosphate homeostasis, acting primarily on bone and kidney to maintain serum calcium levels within a narrow range. PTH also plays important roles in bone remodeling by directly stimulating osteoblasts and osteocytes, integrating its calcemic response with stimulation of bone formation. Through the RANK/RANK-ligand system, these cells activate osteoclasts, promoting a balanced process of bone formation and resorption that maintains bone density and strength. Dysregulation of PTH, as seen in disorders such as hyper- and hypoparathyroidism, can lead to significant clinical complications. In recent years, major advancements have been made in the development of PTH analogs, aimed at leveraging PTH's physiological effects on bone to treat conditions such as osteoporosis and hypoparathyroidism. While PTH promotes both bone formation and bone resorption, the net outcome may be a gain or loss of bone mass, depending largely on the administration pattern of PTH or its analogs. When PTH is given intermittently (for example, as once-daily subcutaneous injection), bone formation is favored. Continuous administration of PTH or chronic elevation of blood PTH levels as seen in primary hyperparathyroidism tend to promote bone resorption. PTH analogs, such as teriparatide (PTH(1-34)) and the PTHrP analog abaloparatide, administered once daily, have significant efficacy in stimulating bone formation, making them valuable options for the treatment of osteoporosis. Given this capacity to improve bone structure, these analogs hold broader therapeutic potential for other skeletal disorders, including fracture healing and oral bone repair, which expands the scope of PTH-based therapies beyond osteoporosis. Long-acting PTH analogs have applications in treating hypoparathyroidism, offering an alternative to conventional treatment with calcium and active vitamin D. This article reviews the molecular mechanisms of approved and emerging PTH-based medicines, their clinical applications, and recent advances in optimizing their therapeutic potential. We also discuss ongoing research aimed at developing next-generation PTH analogs with improved efficacy for skeletal and metabolic disorders.

Keywords: PTH1R; fracture healing; hypoparathyroidism; osteoporosis; parathyroid hormone; small molecule GPCR agonists.